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  • Title: Adrenergic pathways and left ventricular remodeling.
    Author: Dorn GW.
    Journal: J Card Fail; 2002 Dec; 8(6 Suppl):S370-3. PubMed ID: 12555147.
    Abstract:
    BACKGROUND: Cardiac insufficiency, acute or chronic, engenders an increase in systemic and local myocardial sympathetic tone with release of the endogenous sympathetic hormones epinephrine and norepinephrine. These catecholamines activate cardiomyocyte alpha- and beta-adrenergic receptors which, although responsive to the same hormonal ligands, stimulate almost entirely distinct signaling pathways with different end organ results. METHODS: Minute-by-minute cardiac function is regulated by the beta-adrenergic receptor system, coupled to the adenylate cyclase and protein kinase (PK) A pathway via the Gs heterotrimeric G protein. In contrast, activation of alpha-adrenergic receptors and the Gq/phospholipase C/PKC pathway has little acute effect on instantaneous myocardial contractility, but can be a potent stimulus for cardiac hypertrophy. RESULTS: The distinct effects of alpha- and beta-adrenergic pathways in the in vivo heart, which are difficult to dissociate using conventional pharmacologic techniques, have been delineated through the use of cardiac-specific transgenic overexpression of individual components of their respective signaling pathways. Ventricular remodeling resulting from overexpression of alpha-adrenergic receptors or the alpha subunit of the Gq heterotrimeric G protein takes the form of concentric or eccentric hypertrophy without ventricular dilation or myocardial fibrosis. Cardiomyocyte cell size is increased and a panel of hypertrophy-associated embryonic cardiac genes is reexpressed. These phenotypic features are characteristic of pressure overload hypertrophy, and inhibition of Gq signaling can, in fact, prevent pressure overload hypertrophy in mice. Increased signaling through Gq exceeding that which causes hypertrophy results in cardiomyocyte apoptosis and progression from compensated hypertrophy to dilated cardiomyopathy. CONCLUSION: Transgenic overexpression of beta-adrenergic receptors or the alpha subunit of the Gs heterotrimeric G protein results in the expected increase in myocardial contractility, but also causes a progressive cardiomyocyte loss resulting in a delayed fibrotic cardiomyopathy, thus recapitulating the clinical syndrome of catecholamine cardiomyopathy as seen with pheochromocytoma or iatrogenic catecholamine infusion. These effects of beta-adrenergic receptors are concentration-dependent, and appear to be much more severe for the beta 1 than the beta 2 subtype, perhaps because of beta 2 coupling to inhibitory Gi.
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